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Mol. Cell. Biol. 32 (7): 1284-1295

Copyright © 2012 by the American Society for Microbiology. All rights reserved.

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Michelle L. Turski,a,* Donita C. Brady,a Hyung J. Kim,b Byung-Eun Kim,a Yasuhiro Nose,a Christopher M. Counter,a Dennis R. Winge,c, and Dennis J. Thielea

Department of Pharmacology and Cancer Biology, Duke University Medical School, Durham, North Carolina, USA,a Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah, USA,b Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah, USA,c

Received for publication 31 May 2011. Revision received 21 June 2011. Accepted for publication 10 January 2012.

Abstract: Copper (Cu) is essential for development and proliferation, yet the cellular requirements for Cu in these processes are not well defined. We report that Cu plays an unanticipated role in the mitogen-activated protein (MAP) kinase pathway. Ablation of the Ctr1 high-affinity Cu transporter in flies and mouse cells, mutation of Ctr1, and Cu chelators all reduce the ability of the MAP kinase kinase Mek1 to phosphorylate the MAP kinase Erk. Moreover, mice bearing a cardiac-tissue-specific knockout of Ctr1 are deficient in Erk phosphorylation in cardiac tissue. in vitro investigations reveal that recombinant Mek1 binds two Cu atoms with high affinity and that Cu enhances Mek1 phosphorylation of Erk in a dose-dependent fashion. Coimmunoprecipitation experiments suggest that Cu is important for promoting the Mek1-Erk physical interaction that precedes the phosphorylation of Erk by Mek1. These results demonstrate a role for Ctr1 and Cu in activating a pathway well known to play a key role in normal physiology and in cancer.

Address correspondence to Dennis J. Thiele, dennis.thiele{at}

* Present address: CollabRx, Palo Alto, California, USA.

M.L.T. and D.C.B. contributed equally to this study.

Published ahead of print 30 January 2012

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